반응 #640259

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EtOH NH3

3,5-Bis(4-amidino-2-methoxyphenyl)isoxazole dihydrochloride

→

3-(3-Amidinophenyl)-5-(4-amidinophenyl)isoxazole dihydrochloride

용매

EtOH

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후처리

1. 1
   여과The reaction mixture was filtered through Celite
2. 2
   기타the filtrate was evaporated to dryness
3. 3
   workup.ADDITIONwas treated with EtOH/HCl (2 mL)
4. 4
   여과A yellow solid was filtered off (0.13 g, 73% from the aliquot, 13% overall): mp>350° C. (dec.)

실험 절차

5-(4-Amidinophenyl)-3-phenylisoxazole hydrochloride (1) was prepared from 5-(4-cyanophenyl)-3-phenylisoxazole, see Chrisope, D. R. et al., J. Heterocylic Chem., 18(4), 795-798 (1981), (1.70 g, 6.90 mmol) following the general method in benzene, to give a solid (0.82 g, 40%): mp 262-265° C.; 1H NMR (90 MHz) δ 9.63 (br s, 2H), 9.50 (br s, 2H), 8.08 (m, 6H), 7.82 (s, 1H), 7.60 (m, 3H). Anal. (C16H13N3O.HCl.0.2H2O) C, H, N. 3-(4-Amidinophenyl)-5-phenylisoxazole (2) was prepared as immediately above from 3-(4-cyanophenyl)-5-phenylisoxazole, see Chrisope. D. R. et al., J. Heterocylic Chem., 18(4), 795-798 (1981), (2.10 g, 8.50 mmol) to give a solid (0.87 g, 34%): mp 287-292° C.; 1H NMR (90 MHz) δ 9.60 (br s, 3H), 8.13 (m, 6H), 7.94 (s, 1H), 7.60 (m, 3H). Anal. (C16H13N3O.HCl.0.2H2O) C, H, N. 3,5-Bis(4-amidinophenyl)isoxazole dihydrochloride (3) was prepared from nitrile 50a (1.48 g, 5.47 mmol), EtOH (5 mL) and 1,4-dioxane (60 mL). See Dann. O., et al., Liebigs Ann. Chem., 160-194 (1975). The crude imidate (2.31 g, 97%) was filtered off and stirred overnight in EtOH/NH3 (50 mL) to give a white solid (0.84 g, 41%): mp>350° C. (dec., lit.), see Dann, O., et al., Liebigs Ann. Chem., 160-194 (1975); 1H NMR δ 9.55 (br s, 3H), 9.28 (br s, 3H), 8.17 (d, J=8.7 Hz, 4H), 8.05 (d, J=8.1 Hz, 2H), 8.04 (d, J=8.7 Hz, 2H), 8.04 (s, 1H); MS m/z 306 (MH+ of free base); HPLC (Method A) tR 3.96 min (100 area % at 265 nm). Anal. (C17H15N5O.2HCl) C, H, N, Cl. 3,5-Bis[4-(N-isopropyl)amidinophenyl]isoxazole dihydrochloride (4) was prepared from nitrile 50a (2.18 g, 8.05 mmol). An aliquot of the crude imidate (1.20 g, 2.78 mmol) was reacted with isopropylamine (2.2 mL, 26 mmol) in EtOH (25 mL) overnight to give a white powder (0.51 g, 40%): mp 304-307° C.; 1H NMR δ 9.78 (m, 2H), 9.62 (br s, 2H), 9.28 (br s, 2H), 8.16 (d, J=8.3 Hz, 4H), 8.04 (s, 1H), 7.96 (d, J=8.6 Hz, 2H), 7.94 (d, J=8.5 Hz, 2H), 4.12 (m, 2H), 1.30 (d J=6.5 Hz, 2H); MS m/z 390 (MH+ of free base); HPLC (Method A) tR 6.06 min (100 area % at 265 nm). Anal. (C23H27N5O.2HCl.2.75H2O) C, H, N, Cl. 3,5-Bis[4-(2-imidazolinyl)phenyl]isoxazole dihydrochloride (5). An aliquot of the imidate above (1.25 g, 2.86 mmol), was stirred overnight in a mixture of ethylenediamine (3 mL, 45 mmol) and EtOH (25 mL) to give a cream colored solid: (0.66 g, 54%): mp>350° C. (dec.); 1H NMR δ 7.97 (d, J=8.5 Hz, 2H), 7.96 (d, J=8.7 Hz, 2H), 7.85 (d, J=8.7 Hz, 4H), 7.25 (s, 1H), 4.01 (s, 8H); MS m/z 358 (MH+ of free base); HPLC (Method A) tR 4.96 min (100 area % at 290 nm). Anal. (C21H19N5O.2HCl.0.3H2O) C, H, N, Cl. 5-(4-Amidino-2-nitrophenyl)-3-(4-amidinophenyl)isoxazole dihydrochloride (6) was prepared from nitrile 53a (1.57 g, 4.96 mmol) to give a white solid: (0.67 g, 32%): mp>350° C. (dec.); 1H NMR δ 9.78 (br s, 2H), 9.60 (br s 4H), 9.37 (br s, 2H), 8.63 (s, 1H), 8.37 (d, J=8.2 Hz, 1H) 8.26 (d, J=8.1 Hz, 1H), 8.20 (d, J=8.4 Hz, 2H), 8.05 (d, J=8.0 Hz, 2H), 7.95 (s, 1H); MS m/z 351 (MH+ of free base); HPLC (Method A) tR 3.96 min (100 area % at 254 nm). Anal. (C17H14N6O3.2HCl.0.5H2O) C, H, N, Cl. 5-(4-Amidino-2-chlorophenyl)-3-(4-amidinophenyl)isoxazole dihydrochloride (7) was prepared from nitrile 53b (1.53 g, 5.01 mmol) to give a white solid: (0.78 g, 38%): mp>350° C. (dec.); 1H NMR δ 9.71 (br s, 2H), 9.60 (br s, 2H), 9.49 (br s, 2H), 9.38 (br s, 2H), 8.25 (m, 4H); 8.04 (m, 3H), 7.94 (s, 1H); MS m/z 340 (MH+ of free base); HPLC (Method A) tR 4.43 min (100 area % at 265 nm). Anal. (C17H14ClN5O.2HCl.0.4H2O) C, H, N, Cl. 5-(4-Amidino-2-methoxyphenyl)-3-(4-amidinophenyl)isoxazole dihydrochloride (8) was prepared from nitrile 50b (0.55 g, 1.84 g). The crude imidate was then reacted with ammonium carbonate (2.20 g, 22.90 mmol) in EtOH (30 mL) overnight to give a pale yellow solid (0.27 g, 36%): mp 336-337° C.; 1H NMR δ9.40 (br s, 7H), 8.25 (d, J=8.2 Hz, 2H), 8.14 (d, J=8.0 Hz, 1H), 8.02 (d, J=8.5 Hz, 2H), 7.76 (s, 1H), 7.75 (d, J=0.7 Hz, 1H), 7.61 (dd, J=7.6 and 1.0 Hz, 1H), 4.14 (s. 3H), MS m/z 336 (MH+ of free base); HPLC (Method A) tR 4.64 min (100 area % at 265 nm). Anal. (C18H17N5O2.2HCl.1.5H2O) C, H, N, Cl. 3-(4-Amidino-2-nitrophenyl)-5-(4-amidinophenyl)isoxazole dihydrochloride (9) was prepared from nitrile 53c (1.00 g, 3.17 g) to give a white solid (0.32 g, 24%): mp 350° C. (dec.); 1H NMR δ 9.55 (br s, 7H), 8.62 (d, J=1.8 Hz, 1H), 8.33 (dd, J=8.1 and 1.9 Hz, 1H), 8.19 (d, J=8.7 Hz, 2H), 8.15 (d, J=8.1 Hz, 1H), 8.05 (d, J=8.7 Hz, 2H), 7.79 (s, 1H); MS m/z 351 (MH+ of free base); HPLC (Method A) tR 3.77 min (100 area % at 265 nm). Anal. (C17H1N6O3.2HCl.0.5H2O) C, H, N, Cl. 3-(4-Amidino-2-chlorophenyl)-5-(4-amidinophenyl)isoxazole dihydrochloride (10) was prepared from nitrile 53d (1.00 g, 3.28 mmol). The crude product was dissolved in isopropyl alcohol, and the solution was diluted with ether to give a white power (0.55 g, 41%): mp 350° C. (dec.); 1H NMR δ 9.71 (br s, 2H), 9.62 (br s, 2H), 9.49 (br s, 2H), 9.40 (br s, 2H), 8.24 (d, J=8.5 Hz, 2H), 8.21 (s, 1H), 8.06 (d, J=8.9 Hz, 2H), 8.03 (d, J=8.4 Hz, 1H), 7.98 (d, J=8.4 Hz, 1H), 7.85 (s, 1H); MS m/z 340 (MH+ of free base); HPLC (Method A) tR 4.29 min (100 area % at 265 nm). Anal. (C17H14ClN5O.2HCl.H2O) C, H, N, Cl. 3-(4-Amidino-2-methoxyphenyl)-5-(4-amidinophenyl)isoxazole dihydrochloride (11) was prepared by nitrile 53e (0.94 g, 3.16 mmol) to give a white solid (0.35 g, 28%): mp 335-337° C. (dec.); 1H NMR δ 9.48 (br s, 8H), 8.22 (d, J=8.5 Hz, 2H), 8.04 (d, J=8.4 Hz, 2H), 8.03 (d, J=8.0 Hz, 1H), 7.76 (s. 1H). 7.73 (br s, 1H), 7.58 (dd, J=8.1 and 1.3 Hz, 1H), 4.06 (s, 3H); MS m/z 336 (MH+ of free base); HPLC (Method A) tR 4.25 min (100 area % at 290 nm). Anal. (C18H17N5O2.2HCl.1.1H2O) C, H, N, Cl. 3,5-Bis(4-amidino-2-methoxyphenyl)isoxazole dihydrochloride (12). A mixture of N-acetoxy intermediate 55 (1.11 g, 2.31 mmol) and 10% Pd/C (0.60 g, 0.56 mmol) in ACOH and EtOH (100 mL of each) was hydrogenated at 60 psi for 2.5 h. The reaction mixture was filtered through Celite, and the filtrate was evaporated to dryness. An aliquot of the crude product (0.20 g) was suspended in EtOH (50 mL) was treated with EtOH/HCl (2 mL). A yellow solid was filtered off (0.13 g, 73% from the aliquot, 13% overall): mp>350° C. (dec.); 1H NMR δ 9.64 (brs, 2H), 9.62 (brs, 2H), 9.34 (brs, 4H), 8.14 (d, J=8.1 Hz, 1H), 8.02 (d, J=8.0 Hz, 1H), 7.74 (s, 1H), 7.71 (s, 1H), 7.62 (d, J=8.4 Hz, 1H), 7.57 (d, J=8.1 Hz, 1H), 7.56 (s, 1H), 4.12 (s, 3H), 4.05 (s, 3H); MS m/z 366 (MH+ of free base); HPLC (Method A) tR 5.02 min (100 area % at 265 nm). Anal. (C19H19N5O30.2HCl.1.2H2O) C, H, N, Cl. 3-(3-Amidinophenyl)-5-(4-amidinophenyl)isoxazole dihydrochloride (13) was prepared from nitrile 50c (2.62 g, 9.66 mmol). An aliquot (2.27 g, wet) of the imidate was treated with EtOH/NH3 to give an off-white solid (0.19 g, 10%): mp 212-215° C. (dec.); 1H NMR δ 9.52 (br s, 4H), 8.48 (m, 1H), 8.28 (d, J=8.1 Hz, 1H), 8.16 (d, J=8.7 Hz, 2H), 8.08 (s, 1H), 8.07 (d, J=8.7 Hz, 2H), 8.02 (d, J=8.0 Hz, 1H), 7.83 (t, J=7.8 Hz, 1H); MS m/z 306 (MH+ of free base); HPLC (Method A) tR 3.99 min (100 area % at 290 nm). Anal. (C17H15N5O.2HCl.H2O) C, H, N, Cl. 3-[3-(N-Isopropyl)amidinophenyl]-5-[4-(N-isopropyl)amidinophenyl]-isoxazole dihydrochloride (14) was prepared by treatment of an aliquot (2.16 g, wet) of the above imidate with isopropylamine to give a pale yellow crystals (0.85 g, 37%): mp>350° C.; 1H NMR δ 9.75 (br s, 6H), 8.37 (s, 1H), 8.25 (d, J=7.8 Hz, 1H), 8.13 (d, J=8.4 Hz, 2H), 8.13 (s, 1H), 7.98 (d, J=8.5 Hz, 2H), 7.94 (d, J=8.0 Hz, 1H), 7.80 (t, J=7.8 Hz, 1H), 4.19 (m, 2H), 1.32 (d, J=6.2 Hz, 1H), 1.31 (d, J=6.1 Hz, 1H); MS m/z 390 (MH+ of free base); HPLC (Method A) tR 5.92 min (99.0 area % at 265 nm). Anal. (C23H27N5O.2HCl.H2O) C, H, N, Cl. 3-[3-(2-Imidazolinyl)phenyl]-5-[4-(2-imidazolinyl)phenyl]isoxazole dihydrochloride (15) was prepared by prepared by treatment of an aliquot (1.80 g, wet) of the imidate used in the preparation of 13 with ethylenediamine to give a yellow solid (0.80 g, 45%). mp 248-251° C. (dec.); 1H NMR δ 8.85 (m, 1H), 8.27 (m, 4H), 8.15 (m, 3H), 7.86 (t, J=8.0 Hz, 1H), 4.05 (s, 1H), 4.03 (s, 1H); MS m/z 358 (MH+ of free base); HPLC (Method A) tR 4.96 min (100 area % at 290 nm). Anal. (C21H19N5O.2HCl.1.5H2O) C, H, N, Cl. 5-(4-Amidino-2-nitrophenyl)-3-(3-amidinophenyl)isoxazole dihydrochloride (16) was prepared from nitrile 53g (0.50 g, 1.58 mmol) to give a white solid (0.14 g, 21%): mp 225-225° C.; 1H NMR δ 9.84 (br s, 2H), 9.64 (br s, 2H), 9.59 (br s, 2H), 9.37 (br s, 2H), 8.63 (d, J=1.8 Hz, 1H); 8.46 (m, 1H), 8.36 (dd, J=8.1 and 1.8 Hz, 1H), 8.30 (dm, J=8.1 Hz, 1H), 8.24 (d, J=8.1 Hz, 1H), 8.02 (dm, J=8.0 Hz, 1H), 7.92 (s, 1H), 7.84 (t, J=7.8 Hz, 1H); MS m/z 351 (MH+ of free base); HPLC (Method A) tR 4.11 min (100 area % at 230 nm). Anal. (C17H1N6O3.2HCl.1.2H2O) C, H, N, Cl. 5-(4-Amidino-2-chlorophenyl)-3-(3-amidinophenyl)isoxazole dihydrochloride (17) was prepared from nitrile 53h to give a white solid (0.16 g, 23%): mp 242-245° C.; 1H NMR δ 9.72 (br s, 2H), 9.67 (br s, 2H), 9.49 (br s, 2H), 9.40 (br s, 2H), 8.54 (m, 1H), 8.36 (dm, J=8.0 Hz, 1H), 8.25 (d, J=8.0 Hz, 1H), 8.24 (d, J=8.0 Hz, 1H), 8.06 (s, 1H), 8.04 (m, 1H), 8.02 (m, 1H), 7.83 (t, J=7.9 Hz, 1H); MS m/z 340 (MH+ of free base); HPLC (Method A) tR 4.52 min (100 area % at 230 nm). Anal. (C17H14ClN5O.2HCl.0.2H2O) C, H, N, Cl. 5-(4-Amidino-2-methoxyphenyl)-3-(3-amidinophenyl)isoxazole dihydrochloride (18) was prepared from nitrile 50d (0.67 g, 2.47 mmol) to give a white solid (0.12 g, 14%): mp 241-246° C.; 1H NMR δ 9.67 (br s, 4H), 9.37 (br s, 4H), 8.50 (s, 1H), 8.34 (d, J=8.0 Hz, 1H), 8.15 (d, J=8.2 Hz, 1H), 8.01 (d, J=7.8 Hz, 1H), 7.83 (s, 1H), 7.82 (t, J=7.9 Hz, 1H), 7.76 (d, J=1.8 Hz, 1H), 7.62 (dd, J=8.2 and 1.8 Hz, 1H), 4.16 (s, 3H); MS m/z 336 (MH+ of free base); HPLC (Method A) tR 3.92 min (100 area % at 230 nm). Anal. (C18H17N5O.2HCl.1.3H2O) C, H, N, Cl. 3-(5-Amidino-2-nitrophenyl)-5-(4-amidinophenyl)isoxazole dihydrochloride (19) was prepared from nitrile 50e (1.18 g, 3.73 mmol) to give a white solid (0.15 g, 12%): mp 238-240° C.; 1H NMR δ 9.85 (br s, 1H), 9.60 (br s, 3H), 9.35 (br s, 1H), 8.43 (d, J=1.9 Hz, 1H), 8.37 (d, J=8.4 Hz, 1H), 8.25 (dd, J=8.5 and 2.0 Hz, 1H), 8.15 (d, J=8.6 Hz, 2H), 8.06 (d, J=8.7 Hz, 2H), 7.88 (s, 1H); MS m/z 351 (MH+ of free base); HPLC (Method A) tR 4.05 min (100 area % at 265 nm). Anal. (C17H1N6O2.2HCl.1.45H2O) C, H, N, Cl. 3-(5-Amidino-2-chlorophenyl)-5-(4-amidinophenyl)isoxazole dihydrochloride (20) was prepared from nitrile 53j (0.41 g, 1.35 mmol) to give a white solid (0.18 g, 33%): mp 348° C.; 1H NMR δ 9.68 (brs, 2H), 9.61 (brs, 2H), 9.40 (br s, 4H), 8.28 (br s, 1H), 8.21 (d, J=8.5 Hz, 2H), 8.06 (d, J=8.2 Hz, 2H), 8.05 (dd, J=8.5 and 1.9 Hz, 1H), 7.99 (d, J=8.5 Hz, 1H), 7.89 (s, 1H); MS m/z 40 (MH+ of free base); HPLC (Method A) tR 4.55 min (100 area % at 265 nm). Anal. (C17H14ClN5O.2HCl.0.7H2O) C, H, N, Cl. 3-(5-Amidino-2-methoxyphenyl)-5-(4-amidinophenyl)isoxazole dihydrochloride (21) was prepared from nitrile 50f (0.90 g, 2.99 mmol) to give a white solid (0.25 g, 22%): mp 272-275° C.; 1H NMR δ 9.40 (br s, 7H), 8.34 (d, J=2.6 Hz, 1H), 8.21 (d, J=8.7 Hz, 2H), 8.08 (dd, J=8.9 and 2.6 Hz, 1H), 8.05 (d, J=8.1 Hz, 2H), 7.77 (s, 1H), 7.49 (d, J=9.1 Hz, 1H), 4.05 (s, 3H); MS m/z 336 (MH+ of free base); HPLC (Method A) tR 4.31 min (100 area % at 290 nm). Anal. (C18H17N5O2.2HCl.0.8H2O) C, H, N, Cl. 3-(4-Amidinophenyl)-5-(3-amidinophenyl)isoxazole di hydrochloride (22) was prepared from nitrile 50g (1.25 g, 4.61 mmol) to give a white solid (1.02 g, 58%): mp 336-338° C.; 1H NMR δ 9.53 (br s, 8H), 8.48 (br s, 1H), 8.26 (d, J=7.7 Hz, 1H), 8.15 (d, J=8.8 Hz, 2H), 8.05 (d, J=8.8 Hz, 2H), 8.03 (d, J=7.7 Hz, 1H), 8.01 (s, 1H), 7.85 (dd, J=7.7 and 7.7 Hz, 1H); HPLC (Method A) tR 4.09 min (100 area % at 265 nm). Anal. (C17H15N5O.2HCl.2.3H2O) C, H, N, Cl. 3-[4-(N-Isopropyl)amidinophenyl]-5-[3-(N-isopropyl)amidinophenyl]-isoxazole dihydrochloride (23) was prepared from nitrile 50g (0.35 g, 1.28 mmol) to give a white solid (0.22 g, 38%): mp 340-343° C. dec; 1H NMR δ 9.90 (d, J=8.4 Hz, 1H), 9.82 (d, J=7.9 Hz, 1H), 9.73 (brs, 1H), 9.66 (brs, 1H), 9.41 (brs, 1H), 9.35 (brs, 1H), 8.35 (brs, 1H), 8.25 (d, J=7.8 Hz, 1H), 8.14 (d, J=7.9 Hz, 2H), 8.03 (s, 1H), 7.95 (d, J=7.9 Hz, 2H), 7.92 (d, J=7.8 Hz, 1H), 7.82 (dd, J=7.8 and 7.8 Hz, 1H), 4.15 (m, 2H), 1.31 (d, J=6.6 Hz, 6H), 1.30 (d, J=6.6 Hz, 6H); HPLC (Method A) tR 5.97 min (100 area % at 254 nm). Anal. (C23H27N5O.2HCl.1.2H2O) C, H, N, Cl. 3-[4-(2-Imidazolinyl)phenyl]-5-[3-(2-imidazolinyl)phenyl]isoxazole dihydrochloride (24) was prepared from nitrile 48g (0.35 g, 1.28 mmol) to give a white solid (0.39 g, 70. %): mp 315-317° C. dec; 1H NMR δ 10.92 (br s, 4H), 8.75 (brs, 1H), 8.30 (d, J=7.7 Hz, 1H), 8.21 (s, 4H), 8.17 (d, J=7.7 Hz, 1H), 7.99 (br s, 2H), 7.91 (dd, J=7.7 and 7.7 Hz, 1H), 4.06 (m, 8H); HPLC (Method A) tR 5.01 min (100 area % at 265 nm). Anal. (C21H19N5O.2HCl.2H2O) C, H, N, Cl. 5-(5-Amidino-2-chlorophenyl)-3-(4-amidinophenyl)isoxazole dihydrochloride (25) was prepared from nitrile 53k (0.72 g, 2.36 mmol) to give a white solid (0.48 g, 50%): mp 356-358° C. dec; 1H NMR δ 9.75 (br s, 2H), 9.63 (br s, 2H), 9.49 (br s, 2H), 9.41 (br s, 2H), 8.49 (br s, 1H), 8.25 (m, 2H), 8.10-7.95 (m, 5H); HPLC (Method A) tR 4.67 min (100 area % at 254 nm). Anal. (C17H14ClN5O.2HCl.1H2O) C, H, N, Cl. 5-(5-Amidino-2-methoxyphenyl)-3-(4-amidinophenyl)isoxazole dihydrochloride (26) was prepared from nitrile 50h (0.85 g, 2.82 mmol) to give a white solid (0.85 g, 74%): mp 240-242° C.; 1H NMR δ 9.46 (br s, 8H), 8.46 (d, J=2.2 Hz, 1H), 8.24 (d, J=8.8 Hz, 2H), 8.07 (dd, J=8.8 and 2.2 Hz, 1H), 8.04 (d, J=8.8 Hz, 2H), 7.73 (s, 1H), 7.52 (d, J=8.8 Hz, 1H), 4.14 (s, 3H); HPLC (Method A) tR 4.50 min (100 area % at 265 nm). Anal. (C18H17N5O2.2HCl.3.1H2O) C, H, N, Cl. 3-(4-Amidino-2-nitrophenyl)-5-(3-amidinophenyl)isoxazole dihydrochloride (27) was prepared from nitrile 531 (0.78 g, 2.47 mmol) to give a white solid (0.26 g, 25%): mp 236° C. dec; 1H NMR δ 10.0-9.20 (br s, 8H), 8.63 (s, 1H), 8.48 (s, 1H), 8.35 (d, J=8.2 Hz, 1H), 8.28 (d, J=7.7 Hz, 1H), 8.14 (d, J=8.2 Hz, 1H), 8.02 (d, J=7.7 Hz, 1H), 7.85 (dd, J=8.2 and 8.2 Hz, 1H), 7.73 (s, 1H); HPLC (Method A) tR 3.92 min (100 area % at 254 nm). Anal. (C17H14N6O3.2HCl.0.8H2O) C, H, N, Cl. 3-(4-Amidino-2-chlorophenyl)-5-(3-amidinophenyl)isoxazole dihydrochloride (28) was prepared from nitrile 53m (0.77 g, 2.47 mmol) to give a white solid (0.34 g, 33%): mp 210° C. dec; 1H NMR δ 9.58 (br s, 8H), 8.54 (s, 1H), 8.32 (d, J=7.7 Hz, 1H), 8.21 (s, 1H), 8.03 (d, J=7.7 Hz, 1H), 8.02 (d, J=8.2 Hz, 1H), 7.99 (d, J=8.2 Hz, 1H), 7.85 (dd, J=8.2 and 8.2 Hz, 1H), 7.80 (s, 1H); HPLC (Method A) tR 4.41 min (100 area % at 254 nm). Anal. (C17H14ClN5O.2HCl.1.1H2O) C, H, N, Cl. 3-(4-Amidino-2-methoxyphenyl)-5-(3-amidinophenyl)isoxazole dihydrochloride (29) was prepared from nitrile 53n (1.00 g, 3.32 mmol) to give a white solid (0.29 g, 22%): mp 288° C. dec; 1H NMR δ 9.69 (br s, 4H), 9.43 (br s, 4H), 8.52 (s, 1H), 8.30 (d, J=7.7 Hz, 1H), 8.03 (d, J=8.2 Hz, 1H), 8.00 (d, J=7.7 Hz, 1H), 7.82 (dd, J=7.7 and 7.7 Hz, 1H), 7.74 (s, 2H), 7.59 (d, J=8.2 Hz, 1H), 4.08 (s, 3H); HPLC (Method A) tR 4.42 min (100 area % at 265 nm). Anal. (C18H17N5O2.2HCl.1H2O) C, H, N, Cl. 5-(5-Amidino-2-methoxyphenyl)-3-(4-amidino-2-nitrophenyl)isoxazole dihydrochloride (30) was prepared from nitrile 53o (0.70 g, 2.03 mmol) to give a white solid (0.10 g, 11%): mp 260° C. dec; 1H NMR δ 9.70-9.20 (br s, 8H), 8.62 (s, 1H), 8.48 (d, J=1.6 Hz, 1H), 8.34 (d, J=8.2 Hz, 1H), 8.19 (d, J=8.2 Hz, 1H), 8.10 (dd, J=8.8 and 1.6 Hz, 1H), 7.52 (d, J=8.8 Hz, 1H), 7.48 (s, 1H), 4.10 (s, 3H); HPLC (Method A) tR 4.51 min (100 area % at 254 nm). Anal. (C18H16N6O4.2HCl.0.8H2O) C, H, N, Cl. 3-(4-Amidino-2-methoxyphenyl)-5-(5-amidino-2-methoxyphenyl)isoxazole dihydrochloride (31) was prepared from nitrile 53p (0.78 g, 2.35 mmol) to give a white solid (0.36 g, 35%): mp 330° C. dec; 1H NMR δ 9.63 (br s, 2H), 9.48 (br s, 2H), 9.34 (br s, 2H), 9.18 (br s, 2H), 8.44 (d, J=2.2 Hz, 1H), 8.06 (dd, J=8.9 and 2.2 Hz, 1H), 8.02 (d, J=8.1 Hz, 1H), 7.72 (d, J=1.3 Hz, 1H), 7.57 (dd, J=8.1 and 1.3 Hz, 1H), 7.52 (d, J=8.9 Hz, 1H), 7.41 (s, 1H), 4.11 (s, 3H), 4.05 (s, 3H); HPLC (Method A) tR 5.01 min (100 area % at 254 nm). Anal. (C19H19N5O3.2HCl) C, H, N, Cl. 3,5-Bis(3-amidinophenyl)isoxazole dihydrochloride (32) was prepared from nitrile 50i (0.58 g, 2.15 mmol) to give a white solid (0.40 g, 62%): mp 365-367° C.; 1H NMR δ 9.60 (br s, 4H), 9.32 (d, J=6.8 Hz, 4H), 8.42 (br s, 2H), 8.27 (d, J=7.7 Hz, 2H), 7.99 (d, J=7.7 Hz, 2H), 7.96 (s, 1H), 7.86 (t, J=7.7 Hz, 1H), 7.85 (t, J=7.7 Hz, 1H); HPLC (Method A) tR 3.92 min (98.8 area % at 254 nm). Anal. (C17H15N5O.2HCl.2H2O) C, H, N, Cl. 3,5-Bis[3-(N-isopropyl)amidinophenyl]isoxazole dihydrochloride (33) was prepared from nitrile 50i (0.58 g, 2.15 mmol) to give a white solid (0.33 g, 42%): mp 260° C. dec; 1H NMR δ 9.83 (br s, 2H), 9.65 (br s, 2H), 9.29 (d, J=4.1 Hz, 2H), 8.29 (br s, 2H), 8.24 (d, J=7.7 Hz, 2H), 7.98 (s, 1H), 7.86 (m, 4H), 4.09 (m, 2H), 1.31 (d, J=6.6 Hz, 12H); MS m/z 390.5 (MH+ of free base); HPLC (Method A) tR 5.83 min (100 area % at 254 nm). Anal. (C23H27N5O.2HCl.1.5H2O.0.2EtOH) C, H, N, Cl. 3,5-Bis[3-(2-imidazolinyl)phenyl]isoxazole dihydrochloride (34) was prepared from nitrile 50i (0.58 g, 2.15 mmol) to give a white solid (0.37 g, 54%): mp 373-374° C.; 1H NMR δ 11.02 (s, 4H), 8.74 (s, 2H), 8.28 (d, J=7.1 Hz, 2H), 8.19 (d, J=7.7 Hz, 2H), 8.01 (s, 1H), 7.91 (m, 2H), 4.06 (s, 8H); HPLC (Method A) tR 5.00 min (100 area % at 254 nm). Anal. (C21H19N5O.2HCl.0.5H2O) C, H, N, Cl. 5-(5-Amid ino-2-nitrophenyl)-3-(3-amidinophenyl)isoxazole dihydrochloride (35) was prepared from nitrile 50j (0.42 g, 1.33 mmol) to give a white solid (0.05 g, 9%): mp 222° C. dec; 1H NMR δ 9.83 (s, 2H), 9.60 (s, 2H), 9.55 (s, 2H), 9.30 (s, 2H), 8.48 (s, 1H), 8.40 (s, 1H), 8.39 (d, J=8.2 Hz, 1H), 8.26 (m, 2H), 8.00 (d, J=7.7 Hz, 1H), 7.84 (t, J=7.7 Hz, 1H), 7.82 (s, 1H); MS m/z 351 (MH+ of free base); HPLC (Method A) tR 4.35 min (100 area % at 254 nm). Anal. (C17H14N6O3.2HCl.1H2O) C, H, N, Cl. 5-(5-Amidino-2-chlorophenyl)-3-(3-amidinophenyl)isoxazole dihydrochloride (36) was prepared from nitrile 53q (0.50 g, 1.64 mmol) to give a white solid (0.33 g, 58%): mp 347° C. dec; 1H NMR δ 9.67 (s, 2H), 9.62 (s, 2H), 9.38 (s, 2H), 9.32 (s, 2H), 8.48 (d, J=8.8 Hz, 2H), 8.35 (d, J=7.1 Hz, 1H), 7.99 (m, 4H), 7.83 (t, J=7.7 Hz, 1H); HPLC (Method A) tR 4.68 min (100 area % at 254 nm). Anal. (C17H14N5OCl.2HCl.0.3H2O) C, H, N, Cl. 5-(5-Amidino-2-methoxyphenyl)-3-(3-amidinophenyl)isoxazole dihydrochloride (37) was prepared from nitrile 50k (0.19 g, 0.64 mmol) to give a white solid (0.12 g, 46%): mp 240° C. dec; 1H NMR δ 9.66 (s, 2H), 9.47 (s, 2H), 9.34 (s, 2H), 9.18 (s, 2H), 8.47 (m, 2H), 8.34 (d, J=8.2 Hz, 1H), 8.06 (d, J=8.8 Hz, 1H), 8.00 (d, J=7.7 Hz, 1H), 7.81 (t, J=7.7 Hz, 1H), 7.77 (s, 1H), 7.52 (d, J=8.8 Hz, 1H), 4.12 (s, 3H); HPLC (Method A) tR 4.63 min (100 area % at 254 nm). Anal. (C18H17N5O2.2HCl.0.7H2O) C, H, N, Cl. 3-(5-Amidino-2-nitrophenyl)-5-(3-amidinophenyl)isoxazole dihydrochloride (38) was prepared by from nitrile 501 (0.24 g, 0.76 mmol) to give a white solid (0.08 g, 25%): mp 220° C. dec; 1H NMR δ 9.81 (s, 2H), 9.61 (s, 2H), 9.52 (s, 2H), 9.33 (s, 2H), 8.39 (m, 3H), 8.25 (m, 2H), 8.00 (d, J=8.2 Hz, 1H), 7.87 (t, J=7.7 Hz, 1H), 7.72 (s, 1H); MS m/z 351 (MH+ of free base); HPLC (Method A) tR 4.11 min (97.59 area % at 254 nm). Anal. (C17H14N6O3.2HCl.1H2O) C, H, N, Cl. 3-(5-Amidino-2-chlorophenyl)-5-(3-amidinophenyl)isoxazole dihydrochloride (39) was prepared from nitrile 53r (0.60 g, 1.96 mmol) to give a light yellow solid (0.39 g, 48%): mp 239-140° C.; 1H NMR δ 9.66 (s, 4H), 9.40 (s, 4H), 8.50 (s, 1H), 8.30 (d, J=8.2 Hz, 1H), 8.26 (d, J=2.2 Hz, 1H), 8.04 (dd, J=8.2 and 2.2 Hz, 1H), 8.00 (m, 2H), 7.84 (dd, J=8.7 and 7.7 Hz, 1H), 7.80 (s, 1H); HPLC (Method A) tR 4.69 min (100 area % at 254 nm). Anal. (C17H14N5O.2HCl.1.5H2O.0.3EtOH) C, H, N, Cl. 3-(5-Amidino-2-methoxyphenyl)-5-(3-amidinophenyl)isoxazole dihydrochloride (40) was prepared from nitrile 50m (0.34 g, 1.13 mmol) to give a light yellow solid (0.15 g, 33%): mp 210° C. dec; 1H NMR δ 9.64 (s, 2H), 9.42 (s, 2H), 9.35 (s, 2H), 9.12 (s, 2H), 8.47 (s, 1H), 8.33 (d, J=2.2 Hz, 1H), 8.30 (d, J=8.8 Hz, 1H), 8.06 (dd, J=8.2 and 2.2 Hz, 1H), 7.98 (d, J=7.7, 2H), 7.83 (t, J=7.7 Hz, 1H), 7.71 (s, 1H), 7.50 (d, J=8.8 Hz, 1H), 4.05 (s, 3H); HPLC (Method A) tR 4.46 min (100 area % at 254 nm). Anal. (C18H17N5O2.2HCl.0.6H2O) C, H, N, Cl. 3,5-Bis(5-amidino-2-methoxyphenyl)isoxazole dihydrochloride (41) was prepared from nitrile 53s (0.70 g, 2.11 mmol) to give a light yellow solid (0.34 g, 44%): mp 240° C. dec; 1H NMR δ 9.54 (s, 2H), 9.50 (s, 2H), 9.28 (s, 2H), 9.23 (s, 2H), 8.45 (d, J=2.2 Hz, 1H), 8.31 (d, J=2.2 Hz, 1H), 8.09 (dd, J=8.8 and 2.2 Hz, 2H), 7.50 (t, J=8.8 Hz, 2H), 7.43 (s, 1H), 4.11 (s, 3H), 4.03 (s, 3H); HPLC (Method A) tR 5.19 min (96.04 area % at 254 nm). Anal. (C19H19N5O3.2.1HCl.2.2H2O) C, H, N, Cl. 3,5-Bis[5-(N-isopropyl)amidino-2-methoxyphenyl]isoxazole dihydrochloride (42) was prepared from nitrile 53s (0.70 g, 2.11 mmol) to give a white solid (0.33 g, 30%): mp 185° C. dec; 1H NMR δ 9.70 (m, 2H), 9.57 (d, J=10.9 Hz 2H), 9.18 (d, J=13.2 Hz, 2H), 8.31 (d, J=2.2 Hz, 1H), 8.20 (d, J=2.2 Hz, 1H), 7.95 (dd, J=8.8 and 2.2 Hz, 2H), 7.47 (d, J=8.8 Hz, 2H), 7.44 (s, 1H), 4.11 (m, 2H), 4.09 (s, 3H), 4.02 (s, 3H), 1.29 (m, 12H); HPLC (Method A) tR 7.07 min (100 area % at 254 nm). Anal. (C25H31N5O3.2.4HCl.1.6H2O.0.2EtOH) C, H, N, Cl. 3,5-Bis[5-(2-imidazolinyl)-2-methoxyphenyl]isoxazole dihydrochloride (43) was prepared by from nitrile 53s (0.70 g, 2.11 mmol) to give a white solid (0.44 g, 42%): mp 210° C. dec; 1H NMR δ 10.95 (s, 2H), 10.91 (s, 2H), 8.67 (d, J=2.2 Hz, 1H), 8.54 (d, J=2.2 Hz, 1H), 8.33 (dd, J=8.8 and 2.2 Hz, 2H), 7.54 (t, J=8.8 Hz, 2H), 7.47 (s, 1H), 4.12 (s, 3H), 4.04 (s, 3H), 4.01 (s, 4H), 4.00 (s, 4H); HPLC (Method A) tR 6.16 min (100 area % at 254 nm). Anal. (C23H23N5O3.2.2HCl.2.5H2O.0.1 EtOH) C, H, N, Cl. 4-Cyano-2-methoxybenzaldehyde (44f). A solution of silver nitrate (25.0 g, 147 mmol) in water (75 mL) was added dropwise to a solution of α,β-dibromotoluene 65 (18.22 g, 59.74 mmol) in refluxing EtOH (300 mL). The mixture was maintained at reflux for 30 min, filtered and evaporated to dryness. The residue was diluted with water and extracted into EtOAc to give a white solid (9.55 g, 99%): mp 109-111° C.; 1H NMR δ 10.37 (d, J=0.8 Hz, 1H), 7.82 (d, J=7.8 Hz, 1H), 7.80 (d, J=1.0 Hz, 1H), 7.54 (dm, J=7.8 Hz, 1H), 3.99 (s, 3H); HPLC (Method B) tR 3.56 min (100 area % at 254 nm). Anal. (C9H7N5O2) C, H, N.

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